The present invention includes a method for carbamoylating an alcohol with sodium cyanate in the presence of methanesulfonic acid. The reaction can be conducted under anhydrous conditions. This method is suitable for carbamoylating a molecule including both an alcohol moiety and a basic moiety and/or a molecule including both an alcohol moiety and a sulfenyl moiety, such as the sulfenyl alcohol precursor of the antiviral agent Capravirine.
The non-nucleoside reverse transcriptase inhibitor known as Capravirine can be synthesized through a route employing chlorosulfonyl isocyanate (CSI) to convert a penultimate Capravirine sulfenyl alcohol to the corresponding carbamate, Capravirine. CSI carbamoylates alcohols in high yield under desirable conditions, but has special shipping and handling requirements due to being highly reactive with water. In addition, CSI is currently available on commercial scale from only two sources, each of which is outside the U.S. These factors along with safety considerations make CSI undesirable as a reagent for the transformation of an alcohol to a carbamate.
A long-used method for carbamoylating alcohols employs sodium cyanate in the presence of trifluoroacetic acid and an inert solvent. The method achieves high yields with a variety of alcohols, but does not work for all alcohols. This synthesis proceeds through generating cyanic acid in situ by the reaction of sodium cyanate with an acid. A widely cited paper on this method by B. Loev and M. Kormendy (J. Org. Chem. 1963, 28, 3421) describes trifluoroacetic acid (TFA), as opposed to other acids, as necessary for obtaining carbamates in good yield. For example, this paper describes that substitution of methanesulfonic acid for trifluoroacetic acid reduces yields of carbamate to only trace levels.
There remains a need for a method for carbamoylating alcohol moieties in molecules also including a basic moiety and/or a sulfenyl moiety, such as Capravirine, and employing an acid other than trifluoroacetic acid.
The present invention includes a method for carbamoylating an alcohol with sodium cyanate in the presence of methanesulfonic acid. The reaction can be conducted under anhydrous conditions. This method is suitable for carbamoylating a molecule including both an alcohol moiety and a basic moiety, such as the sulfenyl alcohol precursor of the antiviral agent Capravirine. This method is also suitable for carbamoylating a molecule including both an alcohol moiety and a sulfenyl moiety, such as the sulfenyl alcohol precursor of the antiviral agent Capravirine.
In one embodiment, the method includes contacting the alcohol with sodium cyanate in the presence of methanesulfonic acid under anhydrous conditions. In another embodiment, the method carbamoylates an alcohol moiety of a molecule also including a nitrogen heterocycle, a sulfenyl moiety, or both, the method including contacting the molecule with sodium cyanate in the presence of methanesulfonic acid. In an additional embodiment, the method carbamoylates Capravirine sulfenyl alcohol, the method including contacting Capravirine sulfenyl alcohol with sodium cyanate in the presence of methanesulfonic acid. Each of these reactions can be carried out under anhydrous conditions, preferably in an inert solvent, such as acetonitrile. The method can also include quenching the reaction and recovering or purifying a resulting carbamate.
The present invention also includes a method for carbamoylating an alcohol with sodium cyanate, potassium cyanate, cesium cyanate, or a mixture thereof in the presence of acetic acid, sulfuric acid, or a mixture thereof. The reaction can be conducted under anhydrous conditions. This method is suitable for carbamoylating a molecule including both an alcohol moiety and a basic moiety. This method is also suitable for carbamoylating a molecule including both an alcohol moiety and a sulfenyl moiety.
Definitions
As used herein, the term xe2x80x9canhydrousxe2x80x9d refers to a reaction mixture that is very dry, typically including less than about 1 wt-% water, preferably less than about 0.7 wt-% water, preferably less than about 0.5 wt-% water, or, preferably, devoid of water. According to the present invention, anhydrous conditions suitable for carrying out the present method can be obtained by measures known to those of skill in the art. Preferably the starting alcohol is dried using known procedures for drying alcohols to a water content of less than about 0.2 wt-%. Typically, commercially available reagent grades of the solvent (e.g., acetonitrile) and acid (e.g. methanesulfonic acid) can be used without drying. Typically these commercially available solvents and acids are essentially anhydrous.
As used herein, the term xe2x80x9cbasexe2x80x9d refers to any of a large class of compounds with one of more of properties such as bitter taste, slippery feeling in solution, ability to turn litmus paper blue and to cause other indicators to take on characteristic colors, or ability to react with (neutralize) acids to form salts. Such bases include both Lowry-Bronsted bases and Lewis bases. Lowry-Bronsted base refers to any molecular or ionic substance that can combine with a proton (hydrogen ion) to form a new compound. A Lewis base refers to any substance that provides a pair of electrons for a covalent bond with a Lewis acid. As used herein, a xe2x80x9cbasic moietyxe2x80x9d is a fragment of a basic compound, which fragment would be a base if it were a compound itself. A compound including a basic moiety is a base. Bases and basic moieties include nitrogen heterocycles.
As used herein, xe2x80x9cnitrogen heterocyclexe2x80x9d refers to any carbon-containing closed-ring structure that includes a nitrogen atom. Examples of nitrogen heterocycles include pyrrole (azole), 2H-pyrrole, 3H-pyrrole, pyrazole (1,2-diazole), imidazole, 2H-imidazole, 1,2,3-triazole, 1,2,4-triazole, isoxazole, oxazole, thiazole, isothiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole (azoxime), 1,2,5-oxadiazole (furazan), 1,3,4-oxadiazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, 3H-1,2,3-dioxazole, 1,2,4-dioxazole, 1,3,2-dioxazole, 1,3,4-dioxazole, 5H-1,2,5-oxathiazole, pyridine, pyridazine, pyrimidine, pyrazine, piperazine, s-triazine (1,3,5-triazine), as-triazine (1,2,4-triazine), v-triazine (1,2,3-triazine), 4H-1,2-oxazine, 2H-1,3-oxazine, 6H-1,3-oxazine, 6H-1,2-oxazine, 1,4-oxazine, 2H-1,2-oxazine, 4H-1,4-oxazine, 1,2,5-oxathiazine, 1,4-oxazine, o-isoxazine, p-isoxazine, 1,2,5-isoxazine, 1,2,5-oxathiazine, 1,2,6-oxathiazine, 1,4,2-oxadiazine, 1,3,5,2-oxadiazine, morpholine (tetrahydro-p-isoxazine), azepine, 1,2,4-aiazepine, indole, 3H-indole (indolenine), 1H-isoindole, cyclopental[b]pyridine, pyrano[3,4-b]-pyrrole, indazole, indoxazine (benzisoxazole), benzoxazole, anthranil, quinoline, isoquinoline, cinnoline, quinazoline, naphthyridine, pyrido[3,4-b]-pyridine, pyrido[3,2-b]-pyridine, pyrido[4,3-b]-pyridine, 2H-1,3-benzoxazine, 2H-1,4-benzoxazine, 1H-2,3-benzoxazine, 4H-3,1-benzoxazine, 2H-1,2-benzoxazine, 4H-1,4-benzoxazine, carbazole, acridine, quinoxaline, purine, and the like.
As used herein, xe2x80x9csulfenyl groupxe2x80x9d, xe2x80x9csulfenyl moietyxe2x80x9d, or xe2x80x9csulfenylxe2x80x9d refers to a compound including a group having the structure RS-, in which R is an organic moiety but not hydrogen. Sulfenyl groups include sulfides (thioethers). As used herein, xe2x80x9csulfidexe2x80x9d or xe2x80x9cthioetherxe2x80x9d refers to a compound including or group having the structure RSRxe2x80x2, in which R and Rxe2x80x2 are each an organic moiety but not hydrogen.
As used herein, the term xe2x80x9cCapravirine sulfenyl alcoholxe2x80x9d refers to a compound represented by the structural formula: 
As used herein, the term xe2x80x9cCapravirinexe2x80x9d refers to a compound represented by the structural formula: 
As used herein, the term xe2x80x9caboutxe2x80x9d modifying the quantity of an ingredient, the ratios of ingredients, or temperatures employed in the methods of the invention refers to variation in the numerical quantity that can occur, for example, through typical weighing, measuring, liquid handling, drying, or temperature control procedures used for making reaction mixtures in the real world; through inadvertent error in these procedures; through differences in the manufacture, source, or purity of the ingredients employed to carry out the methods; and the like. Whether or not modified by the term xe2x80x9caboutxe2x80x9d, the claims include equivalents to the quantities.
Method of Carbamoylating an Alcohol
The present invention includes a method of carbamoylating an alcohol. In an embodiment the method employs anhydrous conditions and methanesulfonic acid for carbamoylating an alcohol with sodium cyanate. Preferably the alcohol is a moiety of a molecule also including a basic group. Preferably the alcohol is a moiety of a molecule also including either a nitrogen heterocycle, a sulfenyl group, or both. A preferred product of the carbamoylation reaction is a carbamate with a structure otherwise derived from the original alcohol.
In a preferred embodiment, the alcohol is a moiety of the sulfenyl alcohol precursor to the antiviral agent Capravirine. Scheme I, below, illustrates both the precursor and Capravirine. 
In one embodiment, the method employs sodium cyanate in the presence of methanesulfonic acid for carbamoylating an alcohol moiety in a molecule also including a basic group. Preferably, the reaction is carried out under anhydrous conditions. Preferably the alcohol is a moiety of a molecule also including either a nitrogen heterocycle, a sulfenyl group, or both. In a preferred embodiment, the alcohol is a moiety of the sulfenyl alcohol precursor to the antiviral agent Capravirine.
In another embodiment, the method employs sodium cyanate in the presence of methanesulfonic acid for carbamoylating an alcohol moiety in a molecule also including a sulfide or sulfenyl group. Preferably, the reaction is carried out under anhydrous conditions. Preferably the alcohol is a moiety of a molecule also including a nitrogen heterocycle. In a preferred embodiment, the alcohol is a moiety of the sulfenyl alcohol precursor to the antiviral agent Capravirine.
Reaction Conditions
The method of the present invention can be carried out under a range of conditions, which are described in greater detail below.
Controlling the stoichiometry of the reagents can advantageously increase the yield of the desired carbamate product. Controlling this stoichiometry can also advantageously reduce or minimize the yield of the corresponding allophanate impurity. For example, the molar ratio of methanesulfonic acid to the alcohol can be varied over a broad range. Preferred molar ratios of methanesulfonic acid to the alcohol include about 5 to about 20, more preferably about 9 to about 10. By way of further example, the molar ratio of sodium cyanate to the alcohol can be varied over a range. Preferred molar ratios of sodium cyanate to the alcohol include about 1.5 to about 2.0, preferably about 1.6 to about 1.7, more preferably about 1.65. A preferred reaction mixture includes as molar ratios of reagents: methanesulfonic acid to the alcohol at about 9 to about 10; and sodium cyanate to the alcohol at about 1.65. Reagents at these ratios are particularly advantageous for carbamoylating the sulfenyl alcohol precursor of the antiviral agent Capravirine.
The reaction solvent can be selected to advantageously increase the yield of the desired carbamate product. Preferred solvents are inert, readily made anhydrous, or both. Preferred solvents include ethyl acetate, tetrahydrofuran, and acetonitrile. More preferred solvents include acetonitrile.
The reaction temperature can be selected to advantageously increase the yield of the desired carbamate product. The reaction temperature can also be selected to advantageously reduce or minimize the yield of the corresponding allophanate impurity. The reaction temperature can vary over a wide range. Preferred ranges for the reaction temperature include about xe2x88x9225 to about +40xc2x0 C., preferably about xe2x88x9210 to about 0xc2x0 C.
Anhydrous conditions are preferred for carbamoylating alcohols according to the present method. Anhydrous conditions can include the presence of small amounts of water. Preferably, if water is present, the water content is less than about 1 wt-%, preferably less than about 0.7 wt-%, preferably less than about 0.5 wt-%.
According to the present invention, in certain circumstances, the reaction can be run with reagents other than sodium cyanate and methane sulfonic acid. For example, for certain alcohols, carbamoylation can occur with cyanates such as potassium cyanate, cesium cyanate, or a mixture thereof. For certain alcohols, carbamoylation can occur with acids similar to methanesulfonic acid, such as acetic acid, sulfuric acid, or a mixture thereof.
The carbamoylation reaction mixture can be assembled for the reaction and manipulated during the reaction by various methods known to those of skill in the art of running organic reactions. The reaction mixture is ultimately formed by contacting the alcohol with sodium cyanate in the presence of methanesulfonic acid, preferably under anhydrous conditions. Contacting or mixing the reagents provides a reaction mixture suitable for reacting the alcohol and the sodium cyanate. The reaction mixture can be formed by adding reagents in any of several different orders. Preferably, the alcohol, sodium cyanate, and an inert solvent are mixed, followed by adding methanesulfonic acid to this initial mixture. Preferably, cooling the initial mixture reduces its temperature to, for example, about xe2x88x9210xc2x0 C. before adding the methanesulfonic acid. Adding methanesulfonic acid preferably proceeds slowly, e.g., dropwise, while maintaining a reduced temperature, preferably below about 0xc2x0 C.
Following addition of methanesulfonic acid, gentle agitation of the reaction mixture at a reduced temperature allows the reaction to proceed to advantageously high yields. Gentle agitation can be accomplished, for example, by stirring. Preferred reduced temperatures for progress of the reaction include about xe2x88x9210 to about 0xc2x0 C. The reaction can proceed for up to about 8 to about 10 hours, or longer. The duration of the reaction can be monitored or decided by one of skill in the art of running organic reactions.
After the desired time, quenching can stop or slow the carbamoylation reaction. Quenching can be accomplished by any of a variety of methods known to those of skill in the art such as cooling, reducing the concentration of one or more reagents, consuming one or more reagents, or the like. Preferably, quenching includes adding water to the reaction mixture. With or without quenching, any carbamate produced in the reaction can be recovered and/or purified from the reaction mixture by methods known to those of skill in the art of running organic reactions.
The present invention may be better understood with reference to the following examples. These examples are intended to be representative of specific embodiments of the invention, and are not intended as limiting the scope of the invention.